Work

RNA Polymerase 1 inhibitors against African trypanosomes in vitro and in mice

Year: 2026

Type: article

Abstract: ABSTRACT Therapy of human African trypanosomiasis, fatal if not treated, has been greatly improved by orally available and safer fexinidazole, but reliable cure of late-stage central nervous system (CNS) infection remains a challenge. African trypanosomes are unique among eukaryotes in having an RNA Polymerase 1 that transcribes not only rRNA but also mRNA that encodes the abundant variable surface glycoprotein (VSG) that coats the cell membrane of bloodstream-form parasites and allows them to evade host immune defenses. RNA Pol 1 inhibitor BMH-21, an intercalator not associated with DNA damage and a lead for new cancer therapy, has reported activity against the synthesis of rRNA and VSG mRNA in Trypanosoma brucei brucei . We evaluated a library of BMH-21 analogs against bloodstream-form T. b. brucei in vitro and found limited tolerance for structural modification. Striking and time-dependent bimodal dose-response curves indicate these compounds have a complex mechanism of action. Most potent against T. b. brucei was benzopyridoquinazoline Compound 2 , with an EC 50 of 84 nM. Analysis of in vitro pharmacokinetic-pharmacodynamic (PK-PD) relationships by a hollow fiber model system revealed that in T. b. brucei , the kinetic driver of Compound 2 is drug concentration, a finding that was confirmed by dose fractionation in infected mice and that highlights the utility of the in vitro system for assessing antitrypanosomal PK-PD. Although Compound 2 accumulates 20-fold in mouse brain tissue vs plasma, efficacy against CNS T. b. brucei in mice was limited. RNA Pol 1 remains an attractive target for developing new and more selectively toxic antitrypanosomal agents.

Source: Antimicrobial Agents and Chemotherapy

DOI: 10.1128/aac.01492-25